Generating Diversity

Not every drug lead will become a successful drug. Geldaiiamyciii/ for example produced unacceptable he pa to toxicity. The next-gene ration derivative, 

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As the Diels-Alder reactions of 2( lff)-pyrazinones with richly substituted acetylenes can be used to generate diversely substituted pyridines and pyridi-nones, these cyclo additions were investigated under microwave irradiation conditions on the 1,2,3-triazole decorated pyrazinone scaffold. As a proof of concept, the pyrazinones bearing a 1,4-disubstituted-1,2,3-triazole unit, linked via a C-0 bond, were reacted with the symmetrical dienophile dimethyl acetylenedicarboxylate (DMAD), in view of minimizing regioselect-ivity problems (Scheme 28). 

Seidah, N. G. and Chretien, M. Proprotein and prohormone convertases a family of subtilases generating diverse bioactive polypeptides. Brain Res. 848 45-62,1999. 

S. L. Generating diverse skeletons of small molecules combinatorially. 

Burke MD, Berger EM, Schreiber SL. (2003) Generating diverse skeletons of small molecules combinatoriaUy. Science 302 613-618. 

Cherubini E and Conti F. Generating diversity at GABAergic synapses. Trends Neurosci 2002 24 155-162. 

To summarize this section, several research groups have effectively exploited parallels between SwAr strategies leading to [6,7]- and [6,6]-ben-zofused heterocycles and have described complementary reaction protocols suitable for generating diverse combinatorial libraries of benzothiazin-3-ones and quinoxalin-2-ones. 

Figure 1 Polyketide biosynthesis. Polyketide backbones are formed via condensations from acyl-CoA thioesters of carboxylic acids. The (3-ketone which results from each condensation can undergo a series of reductive steps analogous to fatty acid biosynthesis. However, either none or only some of the reductive activities may occur in a given cycle. This allows PKSs to generate diversity through selection of priming and extender units, variation of the reductive cycle, and stereoselectivity. (ACP, acyl carrier protein AT, acyl transferase KS, ketosynthase DH, dehydratase ER, enoylreductase KR, ketoreductase TE, thioesterase.) The structure depicted in the lower right-hand corner is representative of the possible structural variations that can arise during polyketide biosynthesis.

Leid, M., Kastner, R, and Chambon, P., Multiplicity generates diversity in the retinoic acid signalling pathways, Trends. Biochem. Sci., 17, 427, 1992. 

Fig. 31.4. Error-prone PCR for directed evolution of enzymes (A) gene of interest (B) errorprone PCR generating diversity (C) expression of variants and characterization (D) selection of variant with improved trait (E) variant then serves as template for subsequent rounds of evolution.

Fig. 31.5. Gene shuffling using a single gene (1) or a family of genes (2) (A) errorprone PCR generating diversity (B) DNAse treatment (C) homologous recombination of fragments and generation of diversity.

Fig. 1 Self-organization by design involves programming through molecular information storage and supramolecular processing. Self-organization with selection takes advantage of constitutional dynamics to generate diversity and implement constitutional variation to allow for adaptation...

The generic structure of the library is reported in Fig. 6.13 a retrosy nthetic analysis arrived at three acids (e.g., 6.27 only the a-dimethyl was reported as a structure in the original article) as suitable precursors prepared from commercially available materials according to a reported procedure (Fig. 6.13) (112). The cleavage of an ester bond with amines was used to generate diversity and simultaneously release the compounds into solution, and a suitable linker was the 4-hydroxythiophenol linker 6.28 (Fig. 6.13) (113, 114). 

Such selections can be based, for example, on sub-structure similarity/dissimilar-ity calculations, or pharmacophore analyses each approach will generally lead to very different selections, even within a single set of compounds. The detailed concept of generating diversity has already been covered in this book, but it is valuable to review the basic concepts. 

This chapter discusses four important considerations in drug discovery definition of drug targets, generating diversity, definition of lead structures, and qualifying leads for transition to early trials. Many of the examples will be drawn from the realm of cancer chemotherapy, but the principles should be broadly applicable to a wide variety of disease types. 

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